In most tissues and organs, the lymphatic circulation is responsible for the removal of interstitial protein and fluid but the parenchyma of the brain and spinal cord is devoid of lymphatic vessels. On the other hand, the literature is filled with qualitative and quantitative evidence supporting a lymphatic function in cerebrospinal fluid (CSF) absorption. The experimental data seems to warrant a re-examination of CSF dynamics and consideration of a new conceptual foundation on which to base our understanding of disorders of the CSF system. The objective of this paper is to review the key studies pertaining to the role of the lymphatic system in CSF absorption.

Abstract-Collagens are abundant within the atherosclerotic plaque, where they contribute to lesion volume and mechanical stability and influence cell signaling. The discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds to collagen, is expressed in blood vessels, but evidence for a functional role during atherogenesis is incomplete. In the present study, we generated Ddr1 ϩ/ϩ ;Ldlr Ϫ/Ϫ and Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ mice and fed them an atherogenic diet for 12 or 24 weeks. Targeted deletion of Ddr1 resulted in a 50% to 60% reduction in atherosclerotic lesion area in the descending aorta at both 12 and 24 weeks. Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ plaques exhibited accelerated deposition of fibrillar collagen and elastin at 12 weeks compared with Ddr1 ϩ/ϩ ;Ldlr Ϫ/Ϫ plaques. Expression analysis of laser microdissected lesions in vivo, and of Ddr1 Ϫ/Ϫ smooth muscle cells in vitro, revealed increased mRNA levels for procollagen ␣1(I) and ␣1(III) and tropoelastin, suggesting an enhancement of matrix synthesis in the absence of DDR1. Furthermore, whereas plaque smooth muscle cell content was unchanged, Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ plaques had a 49% decrease in macrophage content at 12 weeks, with a concomitant reduction of in situ gelatinolytic activity. Moreover, mRNA expression of both monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 was reduced in vivo, and Ddr1 Ϫ/Ϫ ;Ldlr Ϫ/Ϫ macrophages demonstrated impaired matrix metalloproteinase expression in vitro. These data suggest novel roles for DDR1 in macrophage recruitment and invasion during atherogenesis. In conclusion, our data support a role for DDR1 in the regulation of both inflammation and fibrosis early in plaque development. Deletion of DDR1 attenuated atherogenesis and resulted in the formation of matrix-rich plaques. Key Words: atherosclerosis Ⅲ discoidin domain receptor 1 Ⅲ collagen Ⅲ inflammation Ⅲ macrophage A therosclerosis is a fibroinflammatory disease of the arterial wall. The atherosclerotic plaque is home to multiple cell types, including endothelial cells, smooth muscle cells (SMCs), and bone marrow-derived monocyte/ macrophages, all interacting within a chronically inflamed, lipid-rich, and highly dynamic extracellular matrix microenvironment. Collagens are critical components of the extracellular matrix present within atherosclerotic plaques, where they contribute to lesion volume and can constitute up to 60% of total plaque protein. 1 Collagens also provide mechanical stability to the fibrous cap and protect against plaque rupture, a major cause of the clinical complications associated with atherosclerosis. 2 Furthermore, collagens stimulate diverse cellular responses that are central to plaque development. For example, collagen synthesis and degradation are important for smooth muscle cell migration, 3,4 and degraded type I collagen fragments stimulate the disassembly of focal adhesion complexes in SMCs. 5 By contrast, intact type I collagen inhibits SMC proliferation. 6 Additionally, type I collagen promotes monocyte differentiation ...

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A major pathway by which cerebrospinal fluid (CSF) is removed from the cranium is transport through the cribriform plate in association with the olfactory nerves. CSF is then absorbed into lymphatics located in the submucosa of the olfactory epithelium (olfactory turbinates). In an attempt to provide a quantitative measure of this transport,125I-human serum albumin (HSA) was injected into the lateral ventricles of adult Fisher 344 rats. The animals were killed at 10, 20, 30, 40, and 60 min after injection, and tissue samples, including blood (from heart puncture), skeletal muscle, spleen, liver, kidney, and tail were excised for radioactive assessment. The remains were frozen. To sample the olfactory turbinates, angled coronal tissue sections anterior to the cribriform plate were prepared from the frozen heads. The average concentration of125I-HSA was higher in the middle olfactory turbinates than in any other tissue with peak concentrations achieved 30 min after injection. At this point, the recoveries of injected tracer (percent injected dose/g tissue) were 9.4% middle turbinates, 1.6% blood, 0.04% skeletal muscle, 0.2% spleen, 0.3% liver, 0.3% kidney, and 0.09% tail. The current belief that arachnoid projections are responsible for CSF drainage fails to explain some important issues related to the pathogenesis of CSF disorders. The rapid movement of the CSF tracer into the olfactory turbinates further supports a role for lymphatics in CSF absorption and provides the basis of a method to investigate the novel concept that diseases associated with the CSF system may involve impaired lymphatic CSF transport.

Based on quantitative and qualitative studies in a variety of mammalian species, it would appear that a significant portion of cerebrospinal fluid (CSF) drainage is associated with transport along cranial and spinal nerves with absorption taking place into lymphatic vessels external to the central nervous system. CSF appears to convect primarily through the cribriform plate into lymphatics associated with the submucosa of the olfactory and respiratory epithelium. However, the significance of this pathway for CSF absorption in primates has never been established unequivocally. In past studies, we infused Microfil into the subarachnoid compartment of numerous species to visualize CSF transport pathways. The success of this method encouraged us to use a similar approach in the non-human primate. Yellow Microfil was injected post mortem into the cisterna magna of 6 years old Barbados green monkeys (Cercopithecus aethiops sabeus, n = 6). Macroscopic and microscopic examination revealed that Microfil was (1) distributed throughout the subarachnoid compartment, (2) located in the perineurial spaces associated with the fila olfactoria, (3) present within the olfactory submucosa, and (4) situated within an extensive network of lymphatic vessels in the nasal submucosa, nasal septum and turbinate tissues. We conclude that the Microfil distribution patterns in the monkey were very similar to those observed in many other species suggesting that significant nasal lymphatic uptake of CSF occurs in the non-human primate.

The textbook view that cerebrospinal fluid (CSF) absorption occurs mainly through the arachnoid granulations and villi is being challenged by quantitative and qualitative studies that support a major role for the lymphatic circulation in CSF transport. There are many potential sites at which lymphatics may gain access to CSF but the primary pathway involves the movement of CSF through the cribriform plate foramina in association with the olfactory nerves. Lymphatics encircle the nerve trunks on the extracranial surface of the cribriform plate and absorb CSF. However, the time during development in which the CSF compartment and extracranial lymphatic vessels connect anatomically is unclear. In this report, CSF-lymphatic connections were investigated using the silastic material Microfil and a soluble Evan's blue-protein complex in two species; one in which significant CSF synthesis by the choroid plexus begins before birth (pigs) and one in which CSF secretion is markedly up regulated within the first weeks after birth (rats). We examined a total of 46 pig fetuses at embryonic (E) day E80-81, E92, E101, E110 (birth at 114 days). In rats, we investigated a total of 115 animals at E21 (birth at 21 days), postnatal (P) day P1-P9, P12, P13, P15, P22, and adults. In pigs, CSF-lymphatic connections were observed in the prenatal period as early as E92. Before this time (E80-81 fetuses) CSF-lymphatic connections did not appear to exist. In rats, these associations were not obvious until about a week after birth. These data suggest that the ability of extracranial lymphatic vessels to absorb CSF develops around the time that significant volumes of CSF are being produced by the choroid plexus and further support an important role for lymphatic vessels in CSF transport.

The purpose of this investigation was to enhance our understanding of cerebrospinal fluid (CSF) absorption pathways. To achieve this, Microfil (a coloured silastic material) was infused into the subarachnoid space (cisterna magna) of sheep post mortem, and the relevant tissues examined macroscopically and microscopically. The Microfil was taken up by an extensive network of extracranial lymphatic vessels in the olfactory turbinates. In addition however, Microfil also passed consistently through the dura at the base of the brain. Microfil was noted in the spaces surrounding the venous network that comprises the cavernous sinus, in the adventitia of the internal carotid arteries and adjacent to the pituitary gland. Additionally, Microfil was observed within the endoneurial spaces of the trigeminal nerve and in lymphatic vessels emerging from the epineurium of the nerve. These results suggest several unconventional pathways by which CSF may be removed from the subarachnoid space. The movement of CSF to locations external to the cranium via these routes may lead to its absorption into veins and lymphatics outside of the skull. The physiological importance of these pathways requires further investigation.

Previous studies suggested that a major portion of cerebrospinal fluid (CSF) is absorbed by extracranial lymphatics located in the olfactory turbinates. The objective of this study was to determine the impact of elevated intracranial pressure (ICP) on downstream cervical lymphatic pressures in the rat. Pressures were measured in the deep cervical lymph nodes using a servo-null micropressure system. A catheter was placed in a lateral ventricle and fluid was infused from a reservoir at defined ICPs. When Ringer’s solution was infused, elevations of ICP from 10 to 50 cm H₂O resulted on average in a reduction of diastolic cervical node pressures. In contrast, when a diluted plasma solution (80% plasma in Ringer’s) was infused, downstream diastolic lymphatic pressures increased as ICP was elevated to 50 cm H₂O. These data are consistent with the view that much of the CSF-derived water that convects into the lymphatics is absorbed into the ethmoidal or nodal blood vessels. This study supports the concept of fluid continuity between the subarachnoid space and extracranial lymphatics and suggests that this loss of CSF-derived water may act as a safety mechanism to reduce the volume load to the downstream lymphatic vessels.